oligonucleotide-5320 and Acquired-Immunodeficiency-Syndrome

Inhibition of human immunodeficiency virus (HIV) replication by oligonucleotides is a complex process and may be implemented by an array of antiviral mechanisms. These include inhibition of virus adsorption to the host cell, inhibition of transcription via antisense or as the result of triple helix formation, and inhibition of viral encoded enzymes such as reverse transcriptase and integrase. Since the particular mechanism of HIV inhibition depends on the oligonucleotide (ON) sequence and the ON chemical modifications, the design and synthesis of potent HIV inhibitors has been an important and rewarding focus of ON research. In this era of great concern that HIV may rapidly display resistance to any antiviral compound with one mechanism of viral inhibition, oligonucleotides are potentially attractive alternatives for therapy. Several ONs have entered clinical evaluation in AIDS patients. At present Zintevir, which inhibits both HIV adsorption and HIV integrase, is in phase I/II clinical trials.

Topics: Acquired Immunodeficiency Syndrome; Adsorption; Animals; Anti-HIV Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Design; Drug Evaluation, Preclinical; Gene Expression Regulation, Viral; Genetic Therapy; HIV; HIV Integrase; HIV Integrase Inhibitors; HIV Reverse Transcriptase; Macaca fascicularis; Mice; Mice, SCID; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Oligodeoxyribonucleotides, Antisense; Oligonucleotides; Oligonucleotides, Antisense; Rats; Reverse Transcriptase Inhibitors; RNA, Viral; Thionucleotides; Virus Replication

Viral replication was inhibited in a dose-dependent manner after administration of the phosphorothioate oligonucleotide TTGGGGTT (ISIS 5320) to human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu Thy/Liv mice. Potent in vivo antiviral activity was observed against the T-cell-tropic molecular clone NL4-3; the agent was found to have weak activity against one primary HIV-1 isolate, and the agent was inactive against a second primary isolate.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; Disease Models, Animal; Dose-Response Relationship, Drug; HIV-1; Humans; Mice; Mice, SCID; Oligodeoxyribonucleotides; T-Lymphocytes; Thionucleotides; Virus Replication